A Phase 2 interventional study of Cytarabine and Laboratory Biomarker Analysis in Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome With Isolated Del(5q) and Myelodysplastic/Myeloproliferative Neoplasm, sponsored by Mayo Clinic. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-09-06.
Sponsored by Mayo Clinic · Phase 2, Interventional, and Treatment
This randomized phase II trial studies how well WEE1 inhibitor AZD1775 with or without cytarabine works in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has spread to other places in the body and usually cannot be cured or controlled with treatment. WEE1 inhibitor AZD1775 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving WEE1 inhibitor AZD1775 works better with or without cytarabine in treating patients with advanced acute myeloid leukemia or myelodysplastic syndrome.
PRIMARY OBJECTIVES:
I. To estimate the clinical efficacy of AZD1775 (WEE1 inhibitor AZD1775) in combination with AraC (cytarabine) in patients with newly diagnosed acute myeloid leukemia (AML) by assessing complete response (complete remission [CR] plus CR with incomplete blood count recovery [CRi]) rates.
II. To estimate the clinical efficacy of AZD1775 alone or in combination with AraC in patients with relapsed/refractory AML and hypomethylating agent failure myelodysplastic syndrome (MDS) by assessing complete response (CR plus CRi) rates.
SECONDARY OBJECTIVES:
I. To determine the safety and tolerability of AZD1775 alone or combined with AraC in the study population.
II. To estimate additional measures of clinical benefit (i.e. hematological improvements, transfusion requirements).
III. To measure the duration of response of AZD1775 alone or combined with AraC.
IV. To measure time to response of AZD1775 alone or combined with AraC. V. To measure time to progression of AZD1775 alone or combined with AraC. VI. To measure overall survival of AZD1775 alone or combined with AraC. VII. To measure time to AML (for MDS subjects) of AZD1775 alone or combined with AraC.
TERTIARY OBJECTIVES:
I. To determine the pharmacokinetics (PK) of AZD1775 alone or combined with AraC in the study population.
II. To conduct correlative research studies characterizing underlying molecular events and solidifying putative mechanism of action in vivo and to identify potential pharmacodynamic/biomarkers of response to AZD1775 alone or combined with AraC.
III. To evaluate quality of life (QOL) and patient-reported symptoms in subjects treated with AZD1775 alone or combined with AraC.
OUTLINE: Elderly newly diagnosed patients are assigned to arm A.
ARM A (ELDERLY NEWLY DIAGNOSED PATIENTS): Patients receive cytarabine subcutaneously (SC) twice daily (BID) on days 1-5 and 8-12 and WEE inhibitor AZD1775 orally (PO) daily on days 1-5 and 8-12.
Patients are randomized to 1 of 2 treatment arms.
ARM B: Patients receive cytarabine and WEE1 inhibitor AZD1775 as in Arm A.
ARM C: Patients receive WEE inhibitor AZD1775 PO daily on days 1-5, 8-12, 15-19, and 22-26.
In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3-6 months for 2 years.
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Patient population (histological or cytologically confirmed diagnosis):
Untreated elderly (> 60 years) AML if in the intermediate and poor-risk cytogenetic group and not candidates (as judged by treating doctor of medicine [MD]) for or willing to undergo standard induction therapy (i.e. elderly unfavorable cytogenetic AML) or any untreated AML age > 65 years
Any MDS (>= 18 years) having failed or been intolerant to prior hypomethylating agent (HMA) treatment
Patients with isolated 5q-/5q- syndrome must have failed, not tolerated, or lenalidomide in addition to having failed or been intolerant to HMA treatment
Exclusion Criteria:
Any of the following prior therapies:
Targeted therapies (i.e. kinase inhibitors, =\< 7 days or 5 half-life's whichever is shorter)
Clinically significant heart disease, including the following:
New York Heart Association classification IV cardiovascular disease or symptomatic class III disease
Any of the following:
Subject has had prescription or non-prescription drugs or other products known to be sensitive cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued two weeks prior (alternatively 5 half lives if T1/2 is known) prior to day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug
Patients may not be on an inhibitor of breast cancer resistance protein (BCRP)
Patients receive cytarabine and WEE1 inhibitor AZD1775 as in Arm A.
Drug: Cytarabine · Other: Laboratory Biomarker Analysis · Other: Pharmacological Study · Other: Quality-of-Life Assessment · Other: Questionnaire Administration · Drug: WEE1 Inhibitor AZD1775
Patients receive WEE inhibitor AZD1775 PO daily on days 1-5, 8-12, 15-19, and 22-26.
Other: Laboratory Biomarker Analysis · Other: Pharmacological Study · Other: Quality-of-Life Assessment · Other: Questionnaire Administration · Drug: WEE1 Inhibitor AZD1775
Given SC
Also known as: .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosar-U, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453
Correlative studies
Correlative studies
Ancillary studies
Also known as: Quality of Life Assessment
Ancillary studies
Given PO
Also known as: AZD-1775, AZD1775, MK-1775, MK1775
Complete Response Rate (CR or CRi) Per the National Comprehensive Cancer Network (NCCN) Guidelines or According to Specific Criteria From Expert Panels
Complete response rate will be evaluated over all courses of study treatment. The proportion of CR/CRi responses will be estimated by the number of CR/CRi responses divided by the total number of evaluable patients.
Time frame: Up to 17 months
Clinical Benefit as Measured by the Number of Patients Who Were Not RBC Transfusion-dependent Post-Baseline
Clinical benefit as measured by the number of patients who did not receive a RBC transfusion post-Baseline
Time frame: Up to 17 months
Duration of Response
Duration of response defined for all evaluable patients who have achieved a response as the date at which the patient's earliest best objective status is first noted to be a CR/CRi response to the earliest date progression is documented
Time frame: Up to 17 months
Percentage of Participants With Grade 3 or Higher Adverse Events Considered At Least Possibly Related to Treatment
The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.
Time frame: Up to 30 days post-treatment
Overall Survival
Overall survival time is defined as the time from registration to death due to any cause.
Time frame: From registration to death due to any cause, assessed up to 17 months
Time to Progression, Defined as the Time From Registration to the Earliest Date of Documentation of Disease Progression
Time to progression (TTP) is defined to be the length of time from study registration to a) date of disease progression as defined by section 11.0 of the protocol, or b) last follow-up. If a patient dies without documentation of disease progression, the patient will be considered to have had a tumor progression at the time of death unless there is sufficient documented evidence to conclude no progression occurred prior to death. Time to progression curves were compared via the log-rank test. Progression is defined as a \>25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions compared to pretreatment MRI and/or CT scan.
Time frame: Up to 17 months
Time to Response, Defined as the Time From Registration to the Earliest Date of Documentation of Response
Time to response, defined as the time from registration to the earliest date of documentation of response. The distribution of time to progression will be estimated using the method of Kaplan-Meier.
Time frame: Up to 17 months
Change in Biomarker Levels
Continuous biomarker levels will be explored in a graphical manner including mean plots and plots of change and percent change from baseline and other summary measures. Any potential relationships between the baseline level or change in the level of each biomarker and clinical outcome such as overall response, 6-month progression and survival, and adverse event incidence will be further analyzed using Wilcoxon rank sum tests or logistic regression methods, as appropriate. Association between a dichotomized biomarker and overall response will be assessed using a chi-squared test.
Time frame: Baseline to up to 113 days (after course 4)
Change in Patients' Reported Outcomes as Assessed by the Brief Fatigue Inventory (BFI)
BFI, as well as linear analog scales capturing early satiety, abdominal discomfort, inactivity, concentration problems, numbness/tingling in the hands/feet, night sweats, itching, bone pain, fever, and weight loss will be used.
Time frame: Baseline to 2 years
Change in QOL as Assessed by the European Organization for Treatment and Research of Cancer Quality of Life Questionnaire Core Questionnaire 30
Scale score trajectories over time and changes from baseline over time will be examined using repeated measures or growth curve models, as appropriate, stream plots and mean plots with standard deviation error bars overall. Scores and changes at each cycle will be statistically tested using paired t-tests, and standardized response means (i.e. effect sizes) (mean of the change from baseline scores at a given cycle, divided by the standard deviation of the change scores) will be interpreted (after applying Middel's adjustment) using Cohen's cut-offs.
Time frame: Baseline to 2 years
Pharmacokinetic (PK) Parameters AUC of WEE1 Inhibitor AZD1775
PK will be primarily descriptive.
Time frame: Day 1, course 1; pre-treatment, 30 min, 1 hr, 2 hr, 4 hr, 6hr and 24 hr after WEE1 inhibitor AZD administration
Pharmacokinetic (PK) Parameters Vd of WEE1 Inhibitor AZD1775
PK will be primarily descriptive.
Time frame: Day 1, course 1; pre-treatment, 30 min, 1 hr, 2 hr, 4 hr, 6hr and 24 hr after WEE1 inhibitor AZD administration
Pharmacokinetic (PK) Parameters Cmax of WEE1 Inhibitor AZD1775
PK will be primarily descriptive
Time frame: Day 1, course 1; pre-treatment, 30 min, 1 hr, 2 hr, 4 hr, 6hr and 24 hr after WEE1 inhibitor AZD administration
Pharmacokinetic (PK) Parameters Tmax of WEE1 Inhibitor AZD1775
PK will be primarily descriptive
Time frame: Day 1, course 1; pre-treatment, 30 min, 1 hr, 2 hr, 4 hr, 6hr and 24 hr after WEE1 inhibitor AZD administration
Pharmacokinetic (PK) Parameters t1/2 of WEE1 Inhibitor AZD1775
PK will be primarily descriptive
Time frame: Day 1, course 1; pre-treatment, 30 min, 1 hr, 2 hr, 4 hr, 6hr and 24 hr after WEE1 inhibitor AZD administration
| Milestone | Arm A + Arm C (AZD1775 Combined With AraC OR AZD1775 Only) |
|---|---|
| Started | 3 |
| Completed | 3 |
| Not completed | 0 |
Complete response rate will be evaluated over all courses of study treatment. The proportion of CR/CRi responses will be estimated by the number of CR/CRi responses divided by the total number of evaluable patients.
| percentage of patients | Arm A + Arm C (AZD1775 Combined With AraC OR AZD1775 Only) |
|---|---|
| Complete Response Rate (CR or CRi) Per the National Comprehensive Cancer Network (NCCN) Guidelines or According to Specific Criteria From Expert Panels | 0 |
Clinical benefit as measured by the number of patients who did not receive a RBC transfusion post-Baseline
| Participants | Arm A + Arm C (AZD1775 Combined With AraC OR AZD1775 Only) |
|---|---|
| Clinical Benefit as Measured by the Number of Patients Who Were Not RBC Transfusion-dependent Post-Baseline | 0 |
Duration of response defined for all evaluable patients who have achieved a response as the date at which the patient's earliest best objective status is first noted to be a CR/CRi response to the earliest date progression is documented
No measurements were reported for this outcome.
The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.
| percentage of patients | Arm A + Arm C (AZD1775 Combined With AraC OR AZD1775 Only) |
|---|---|
| Percentage of Participants With Grade 3 or Higher Adverse Events Considered At Least Possibly Related to Treatment | 100 |
Overall survival time is defined as the time from registration to death due to any cause.
| months | Arm A + Arm C (AZD1775 Combined With AraC OR AZD1775 Only) |
|---|---|
| Overall Survival | 6 (4.6 to 7.0) |
Time to progression (TTP) is defined to be the length of time from study registration to a) date of disease progression as defined by section 11.0 of the protocol, or b) last follow-up. If a patient dies without documentation of disease progression, the patient will be considered to have had a tumor progression at the time of death unless there is sufficient documented evidence to conclude no progression occurred prior to death. Time to progression curves were compared via the log-rank test. Progression is defined as a \>25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions compared to pretreatment MRI and/or CT scan.
| months | Arm A + Arm C (AZD1775 Combined With AraC OR AZD1775 Only) |
|---|---|
| Time to Progression, Defined as the Time From Registration to the Earliest Date of Documentation of Disease Progression | 3.9 (3.8 to 6.9) |
Time to response, defined as the time from registration to the earliest date of documentation of response. The distribution of time to progression will be estimated using the method of Kaplan-Meier.
No measurements were reported for this outcome.
Continuous biomarker levels will be explored in a graphical manner including mean plots and plots of change and percent change from baseline and other summary measures. Any potential relationships between the baseline level or change in the level of each biomarker and clinical outcome such as overall response, 6-month progression and survival, and adverse event incidence will be further analyzed using Wilcoxon rank sum tests or logistic regression methods, as appropriate. Association between a dichotomized biomarker and overall response will be assessed using a chi-squared test.
Results for this outcome have not been posted.
BFI, as well as linear analog scales capturing early satiety, abdominal discomfort, inactivity, concentration problems, numbness/tingling in the hands/feet, night sweats, itching, bone pain, fever, and weight loss will be used.
Results for this outcome have not been posted.
Scale score trajectories over time and changes from baseline over time will be examined using repeated measures or growth curve models, as appropriate, stream plots and mean plots with standard deviation error bars overall. Scores and changes at each cycle will be statistically tested using paired t-tests, and standardized response means (i.e. effect sizes) (mean of the change from baseline scores at a given cycle, divided by the standard deviation of the change scores) will be interpreted (after applying Middel's adjustment) using Cohen's cut-offs.
Results for this outcome have not been posted.
PK will be primarily descriptive.
Results for this outcome have not been posted.
PK will be primarily descriptive.
Results for this outcome have not been posted.
PK will be primarily descriptive
Results for this outcome have not been posted.
PK will be primarily descriptive
Results for this outcome have not been posted.
PK will be primarily descriptive
Results for this outcome have not been posted.
Collected over Up to 30 days post-treatment. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Arm A + Arm C (AZD1775 Combined With AraC OR AZD1775 Only) | 3/3 (100%) | 3/3 (100%) | 3/3 (100%) |
| Event | Arm A + Arm C (AZD1775 Combined With AraC OR AZD1775 Only) |
|---|---|
| Febrile neutropeniaBlood and lymphatic system disorders | 3/3 |
| Lung infectionInfections and infestations | 2/3 |
| Abdominal painGastrointestinal disorders | 1/3 |
| Gastrointestinal disorders - Other, specifyGastrointestinal disorders | 1/3 |
| FatigueGeneral disorders | 1/3 |
| SepsisInfections and infestations | 1/3 |
| Event | Arm A + Arm C (AZD1775 Combined With AraC OR AZD1775 Only) |
|---|---|
| AnemiaBlood and lymphatic system disorders | 3/3 |
| FatigueGeneral disorders | 3/3 |
| Neutrophil count decreasedInvestigations | 3/3 |
| Platelet count decreasedInvestigations | 3/3 |
| White blood cell decreasedInvestigations | 3/3 |
| DiarrheaGastrointestinal disorders | 2/3 |
| NauseaGastrointestinal disorders | 2/3 |
| FeverGeneral disorders | 2/3 |
| Alanine aminotransferase increasedInvestigations | 2/3 |
| HypokalemiaMetabolism and nutrition disorders | 2/3 |
Since only one patient was accrued on one arm, patient confidentiality prevents the reporting of results by arm.
| Age, Continuous(years) | Arm A + Arm C (AZD1775 Combined With AraC OR AZD1775 Only) |
|---|---|
| Mean | 75.7 ± 1.5 |
| Sex: Female, Male(Participants) | Arm A + Arm C (AZD1775 Combined With AraC OR AZD1775 Only) |
|---|---|
| Female | 1 |
| Male | 2 |
| Race (NIH/OMB)(Participants) | Arm A + Arm C (AZD1775 Combined With AraC OR AZD1775 Only) |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 1 |
| White | 2 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| ECOG Performance Status(Participants) | Arm A + Arm C (AZD1775 Combined With AraC OR AZD1775 Only) |
|---|---|
| 0 | 1 |
| 2 | 2 |
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